Resistant Superbugs Meet Natural Foe in Phage Therapy

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Phages on the surface of an Escherichia coli cell inject genetic material into the bacterium. [NIH]

When people get sick, they often think of bacteria as the cause of their illness and wouldn’t even begin to think of bacteria as having the capability of becoming infected themselves. Yet, scientists have known for decades about viruses that specifically attack bacteria—called bacteriophages or phages for short. Originally proposed as a therapeutic tool by French-Canadian microbiologist Félix d'Herelle in 1926, looking at these viral invaders again may help solve the growing problem of bacterial infections that are resistant to antibiotic treatment.

"Our research team set out to determine whether phages can be effective at killing a large group of bacteria that have become resistant to antibiotics and cause deadly diseases in people," explained senior study investigator Anthony Maresso, Ph.D., associate professor of molecular virology and microbiology at Baylor. "We are running out of available options to treat patients who have these deadly bacterial infections—we need new ideas."

According to the National Institute of General Medical Sciences, sepsis affects more than 1 million people in the United States every year. About 50% of patients with sepsis die—outnumbering the U.S. deaths caused by prostate cancer, breast cancer, and AIDS combined. Antibiotic treatment usually can control bacterial growth and prevent the deadly consequences of sepsis, but an increasing number of bacteria are becoming resistant to antibiotics. As resistance continues to climb, the number of sepsis cases per year is increasing, which underscores the need for new strategies to fight bacterial infections.

"The driving force behind this project was to find phages that would kill 12 strains of antibiotic-resistant bacteria that were isolated from patients," noted co-author Robert Ramig, Ph.D., professor of molecular virology and microbiology at Baylor. "As the virologist on the team, my first contribution was to go phage hunting. I have a number of phages in my lab, but none of them killed the antibiotic-resistant Escherichia coli we were working on—the sequence type 131, currently pandemic across the globe."

Interestingly, birds and dogs often carry the bacteria the researchers were interested in, and may be one environmental reservoir of these pathogens. They also carry phages specific for those bacteria, so the research team went phage hunting in local parks and bird refuges to collect avian and canine feces.

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Bacteriophages can potentially be used to combat antibiotic-resistant bacterial infections. [Sabrina Green/Baylor College of Medicine]

"We isolated a number of phages from animal feces," said Dr. Ramig. "No single phage would kill all the 12 bacterial strains, but collectively two or three of those phages would be able to kill all of those bacteria in cultures in the lab."

This allowed the researchers to move on to the next step—determining whether the phages also would be able to kill the antibiotic-resistant bacteria in an animal model of sepsis. One of the animal models the researchers worked with mimics how cancer patients develop potentially life-threatening infections during their cancer treatment.

"A number of cancer patients who undergo chemotherapy sometimes develop infections that come from bacteria that normally live in their own gut, usually without causing any symptoms," remarked lead study author Sabrina Green, a graduate student in the molecular virology program at Baylor. "Chemotherapy is intended to kill cancer cells, but one of the side effects is that it suppresses the immune system. A suppressed immune system is a major risk factor for infections with these bacteria, which sometimes also are multidrug resistant."

Using immunosuppressed mice, the researchers were able to determine if the phage viruses could keep the antibiotic-resistant bacteria in check.

"When the phages were delivered into the animals, their efficacy in reducing the levels of bacteria and improving health was dramatic," Dr. Maresso stated. "What is remarkable is that these 'drugs' were discovered, isolated, identified, and tested in a matter of weeks, and for less money than most of us probably spend in a month on groceries."

Phages are very specific for certain species or strains of bacteria but can be made broadly acting via cocktails, if desired. Thus, unlike antibiotics, using phages may not be associated with some of the side effects observed, such as clearing beneficial intestinal microbiota. They also don't infect human cells. Another advantage over antibiotics is that phages can evolve. Should resistance develop against one set of phages, new phages can be identified in the environment or evolved in the laboratory in a matter days.

"On the other hand, an antibiotic is a chemical; it cannot change in real time," Dr. Maresso concluded. "It may take years to develop a new antibiotic and at costs that can run into the billions. But a phage can evolve to efficiently kill a resistant strain and then be propagated. It gives me great personal satisfaction when I think of the irony of this—the next antibacterial treatment may use the very same mechanisms bacteria have been using against us for 60-plus years now."